International gestational age-specific centiles for blood pressure in pregnancy from the INTERGROWTH-21st Project in 8 countries: A longitudinal cohort study.

BACKGROUND: Gestational hypertensive and acute hypotensive disorders are associated with maternal morbidity and mortality worldwide. However, physiological blood pressure changes in pregnancy are insufficiently defined. We describe blood pressure changes across healthy pregnancies from the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) Fetal Growth Longitudinal Study (FGLS) to produce international, gestational age-specific, smoothed centiles (third, 10th, 50th, 90th, and 97th) for blood pressure. METHODS AND
FINDINGS: Secondary analysis of a prospective, longitudinal, observational cohort study (2009 to 2016) was conducted across 8 diverse urban areas in Brazil, China, India, Italy, Kenya, Oman, the United Kingdom, and the United States of America. We enrolled healthy women at low risk of pregnancy complications. We measured blood pressure using standardised methodology and validated equipment at enrolment at <14 weeks, then every 5 ± 1 weeks until delivery. We enrolled 4,607 (35%) women of 13,108 screened. The mean maternal age was 28·4 (standard deviation [SD] 3.9) years; 97% (4,204/4,321) of women were married or living with a partner, and 68% (2,955/4,321) were nulliparous. Their mean body mass index (BMI) was 23.3 (SD 3.0) kg/m2. Systolic blood pressure was lowest at 12 weeks: Median was 111.5 (95% CI 111.3 to 111.8) mmHg, rising to a median maximum of 119.6 (95% CI 118.9 to 120.3) mmHg at 40 weeks' gestation, a difference of 8.1 (95% CI 7.4 to 8.8) mmHg. Median diastolic blood pressure decreased from 12 weeks: 69.1 (95% CI 68.9 to 69.3) mmHg to a minimum of 68.5 (95% CI 68.3 to 68.7) mmHg at 19+5 weeks' gestation, a change of -0·6 (95% CI -0.8 to -0.4) mmHg. Diastolic blood pressure subsequently increased to a maximum of 76.3 (95% CI 75.9 to 76.8) mmHg at 40 weeks' gestation. Systolic blood pressure fell by >14 mmHg or diastolic blood pressure by >11 mmHg in fewer than 10% of women at any gestational age. Fewer than 10% of women increased their systolic blood pressure by >24 mmHg or diastolic blood pressure by >18 mmHg at any gestational age. The study's main limitations were the unavailability of prepregnancy blood pressure values and inability to explore circadian effects because time of day was not recorded for the blood pressure measurements.
CONCLUSIONS: Our findings provide international, gestational age-specific centiles and limits of acceptable change to facilitate earlier recognition of deteriorating health in pregnant women. These centiles challenge the idea of a clinically significant midpregnancy drop in blood pressure.

Introduction

Monitoring blood pressure is a key part of antenatal care. Gestational hypertensive disorders result in over 70,000 maternal deaths annually worldwide [1]. However, physiological changes in blood pressure from early pregnancy onwards are not included in any contemporary definition. Instead, the International Society for Study of Hypertension in Pregnancy (ISSHP) uses a threshold to define gestational hypertensive disorders (including preeclampsia) as the new onset of systolic ≥140 mmHg or diastolic ≥90 mmHg blood pressure at or after 20 weeks’ gestation [1]. There is no clear definition of hypotension in pregnancy [2], although it predicts evolving sepsis [3] and is associated with pulmonary embolism [4] and cardiac disease [5], leading causes of maternal mortality [5].

Not incorporating pregnancy-induced physiological changes in the definitions of gestational hyper- or hypotension is understandable. The extent of “normal” measures for each gestational age are not available. Obstetric textbooks [6,7] and e-learning packages [8] commonly report a midpregnancy dip of 10 to 15 mmHg for diastolic blood pressure. This would suggest that thresholds for hypotension should be lower in midpregnancy. However, this paradigm of blood pressure in pregnancy is derived from old studies with small patient numbers [9,10] or comparing mid-second trimester measures with those obtained in prepregnancy (which are often not available in routine clinical practice) rather than in the first trimester [11].

Larger studies including the Avon Longitudinal Study of Parents and Children (ALSPAC) suggest a smaller drop in mean arterial pressure (MAP) between the initial and midpregnancy blood pressures; however, those data are also dated and comprise routinely collected measures from a single geographical region [12].

To fill the knowledge gap for healthy pregnant women, free from major identifiable medical, nutritional, social, and environmental risk factors, with good maternal, perinatal, and child health outcomes, we describe blood pressure patterns from 12 weeks’ gestation to delivery in a secondary analysis of the International Fetal and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) Fetal Growth Longitudinal Study (FGLS) [13]. We also determined whether site blood pressure data could be pooled to generate international gestational age-specific centiles for blood pressure to complement the international standards already published by the INTERGROWTH-21st Project [14].

Defining centiles for systolic and diastolic blood pressure across healthy pregnancies would help determine gestational hypertensive disorders, as well as hypotension thresholds beyond which conditions such as pregnancy-related sepsis and haemorrhage should be considered. These could be incorporated into blood pressure thresholds for Modified Obstetric Early Warning Scores (MOEWS).

Methods

This work is reported following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [15] (S1 STROBE Checklist).

Study design

The INTERGROWTH-21st Project principally aimed to evaluate growth, health, nutrition, and development from less than 14 weeks’ gestation to 2 years of age, using the conceptual framework of WHO Multicentre Growth Reference Study (MGRS) [16]. For the current analysis, we used blood pressures that were taken as part of the study protocol.

Setting

The INTERGROWTH-21st Project was carried out from 2009 to 2016 across 8 diverse geographically delimited urban areas: Pelotas (Brazil), Turin (Italy), Muscat (Oman), Oxford (United Kingdom), Seattle (United States of America), Shunyi County in Beijing (China), central Nagpur (India), and the Parklands suburb of Nairobi (Kenya). Area and hospital selection has been previously described [13]. Women receiving antenatal care had to plan to deliver in these institutions or in a similar hospital located in the same geographical area.

Participants

Participants were selected based upon WHO criteria for optimal health, nutrition, education, and socioeconomic status needed to construct international standards [13]. Women aged ≥18 and <35 years old with a body mass index (BMI) <30 kg/m2 and height ≥153 cm, at low risk of adverse maternal and perinatal outcomes, who commenced antenatal care before 14 weeks’ gestation with reliable menstrual dates, and a confirmatory ultrasound dating scan and provided written informed consent are the FGLS population. Exclusion criteria included hypertension (defined as systolic ≥140 mmHg or diastolic ≥90 mmHg) in a previous pregnancy or the first trimester of the present pregnancy; chronic hypertension on treatment; and a past history of preeclampsia, eclampsia, or haemolysis, elevated liver enzymes and low platelets (HELLP) syndrome.

FGLS also excluded women whose pregnancies became complicated by a priori specified criteria including fetal death, congenital abnormality, severe or catastrophic medical morbidity not evident at enrolment (such as cancer or HIV), severe unanticipated conditions related to the pregnancy that required admission to hospital (such as severe preeclampsia or eclampsia), and those identified during the study who no longer fulfilled entry criteria (such as women who started smoking or had a malaria episode) [13].

Bias

Entry criteria for FGLS were chosen to balance the strict WHO-recommended criteria for selecting a healthy population with external validity of the results [13].

Variables, data sources, and measurement

Gestational age was calculated from the last menstrual period (LMP) date, provided it was certain; the woman had a regular 24- to 32-day menstrual cycle; she had not been using hormonal contraception or breastfeeding in the preceding 2 months; and any discrepancy between the gestational ages based on LMP and crown rump length (CRL), measured by ultrasound between 9 and 13+6 weeks’ gestation, was ≤7 days. The ultrasound dating scan was undertaken using standard study criteria for measuring CRL [13].

The instruction manual for measurement techniques, methods for multicentre standardisation of measures, and procedures for equipment calibration and maintenance is published [17]. All documentation, protocols, data collection forms, and electronic transfer strategies are available at www.intergrowth21.org. Trained research personnel measured systolic and diastolic blood pressure using an automated machine validated in pregnancy (Microlife Blood Pressure Monitor for Pregnant Women, Microlife USA, Florida, USA) with an appropriately sized cuff on study entry between 9 and 13+6 weeks’ gestation and every 5 ± 1 weeks until delivery (i.e., from enrolment, blood pressure was measured in the gestational age windows 14 to 18, 19 to 23, 24 to 28, 29 to 33, 34 to 38, and 39 to 42 weeks).

Study size

The sample size for FGLS was based on practical and statistical considerations [18]. FGLS established an average sample of 500 pregnant women per study site, after exclusion of complicated pregnancies (approximately 3%) and those lost to follow-up (estimated to be 3%, S1 Text). This sample size was adequate to explore site-specific differences [18].

Quantitative variables

We included all recorded blood pressures from all participants in the main analysis and constructed smoothed centiles for systolic and diastolic blood pressure by gestational age. We modelled blood pressure at fortnightly gestational age windows from 12 to 40 weeks. We constructed international, gestational age-specific, smoothed centiles for blood pressure following WHO recommendations [19].

Statistical methods

We included a statistical analysis plan in our application to use data from the INTERGROWTH-21st Project (S2 Text). We assessed variation in systolic and diastolic blood pressure between sites [18] to explore whether we could pool data. We used analysis of variance (ANOVA) to calculate the percentage of variance in the longitudinal blood pressure measures from variance between sites adjusted for gestational age (fixed effects). We treated sites and individuals as random effects. We calculated a standardised site difference (SSD, similar to a z score) as the difference between the mean of 1 site and the mean of all sites. We expressed differences as a proportion of the all sites’ standard deviation (SD) at each corresponding gestational age. The SSD allows direct comparisons across gestational age windows. A priori, we specified an overall value of £ 0.5 SSD as adequate for combining data from all sites [18], as described previously for the construction of international standards in WHO MGRS and INTERGROWTH-21st studies [14]. We undertook a post hoc analysis of the effect of removing outlying sites (with SSDs >0.5).

We estimated blood pressure centiles from generalised additive models for location, scale, and shape (GAMLSS) framework. We assessed different distributions for both systolic and diastolic blood pressure within the GAMLSS framework. This included Box-Cox Cole and Green, Box-Cox Power Exponential, Box-Cox-t, Skew Power Exponential type 3, Skew t type 3, and Power Exponential. We used penalised splines and fractional polynomials to create smooth centiles across the gestational age range. We chose the best fitting distribution based on model fit (Akaike information criterion and Bayesian information criterion) and a comparison of fitted versus empirical centiles. We chose the same distribution for all subgroups within any given blood pressure.

We estimated the precision of the centiles via bootstrapping, by repeatedly sampling and analysing the dataset 50 times. We used the SD of those bootstrapped estimates to calculate the 95% confidence interval for each centile at 2-week intervals. We used the R (version 3·4; R Foundation, Vienna, Austria, www.r-project.org) and GAMLSS (version 4·3–3; R Foundation, www.gamlss.com) packages for all analyses.

We conducted a post hoc sensitivity analysis to assess the effect of excluding women who developed hypertension (defined as systolic ≥140 mmHg or diastolic ≥90 mmHg at any antenatal visit), constructing gestational age-specific centiles for blood pressure in women who remained normotensive (blood pressure <140/90 mmHg).

Finally, we performed post hoc analyses to explore changes in systolic and diastolic blood pressure by baseline for all women and by blood pressure quartile. Our statistical analysis plan included further subgroup analyses (booking BMI, booking BP, and maternal age), which will be considered in future publications.

Loss to follow-up and missing data

Where a woman did not contribute blood pressure measures within one of the possible gestational age windows (14 to 18, 19 to 23, 24 to 28, 29 to 33, 34 to 38, and 39 to 42 weeks), we included all those available. Where women did not complete the study but we knew the final outcome, we included all the data available unless consent for data use was withdrawn.

Ethical approval

The INTERGROWTH-21st Project was approved by Oxfordshire Research Ethics Committee “C” (reference: 08/H0606/139), research ethics committees of the individual institutions, and relevant regional health authorities.

Results

Participants

The enrolment strategy and eligibility criteria of the INTERGROWTH-21st Project, at population and individual level, are published [13]. In brief, 13,108 pregnant women were screened at <14 weeks’ gestation. Of these, 4,607 (35%) met eligibility criteria, provided written informed consent, and were enrolled. Common exclusion reasons were maternal height <153 cm (1,022/8,501; 12%), BMI 330 kg/m2 (1,009/8,501; 12%), and age <18 or >35 years (915/8,501; 11%) at screening. During pregnancy, 71 women (2%) were lost to follow-up or withdrew consent. A total of 36 were excluded (29 had severe medical conditions, 6 took up smoking, and 1 used recreational drugs). Moreover, 4,422 women delivered a live-born singleton. Of these, 4,321 (98%) had a baby without a congenital malformation, (Fig 1), the same cohort that contributed to the INTERGROWTH-21st Fetal Growth Standards [14].

Fig 1

Flow diagram illustrating women enrolled in FGLS.

FGLS, Fetal Growth Longitudinal Study.

Descriptive data

The published sociodemographic characteristics [14] were similar across sites (Table A in S3 Text). The mean maternal age was 28.4 (SD 3.9) years; 97% (4,204/4,321) of women were married or living with a partner, and 68% (2,955/4,321) were nulliparous. Their mean BMI was 23.3 (SD 3.0) kg/m2. The median gestational age at the first antenatal visit was 11.8 (SD 1.4) weeks.

Maternal and perinatal outcome data

Maternal and perinatal outcome data have been published [20]. In brief, 132 (3%) developed gestational hypertension and 31 (<1%) preeclampsia. The spontaneous initiation of labour, preterm birth, term low birth weight, cesarean section, and neonatal mortality rates were 66.4%, 4.5%, 3.0%, 35.7%, and 0.2%, respectively.

Main results

Blood pressure was measured a median of 6 (range = 1 to 7) times throughout pregnancy, resulting in 25,027 blood pressure measures. Within-site systolic and diastolic blood pressure variation (36.6% and 38.4%) was around 6 times higher than between sites variation (6.3% and 6.6%). The all sites’ SD for systolic and diastolic blood pressure ranged from 10.3 and 7.6 mmHg, respectively, at 9 to 13+6 weeks to 11.6 and 8.5 mmHg, respectively, at 34 to 40+6 weeks’ gestation.

Within 6 gestational age windows from 9 to 40+6 weeks, representing 48 comparisons per blood pressure, 39 (systolic) and 42 (diastolic) had SSDs <0.5 (as prescribed a priori in the INTERGROWTH-21st Study Protocol [18]) of the SD of all sites combined (Figs 2 and 3, Table B in S3 Text). Of the 9 comparisons of systolic blood pressure that were ≥0.5 SSD, the sites in India and the UK contributed 5 and 4, respectively, although the difference was <0.5 for both sites at 9 to 13+6 weeks’ gestation (−0·12 and 0.33, respectively; Fig 2). Of the 6 comparisons of diastolic blood pressure that were >0.5 SSD, sites in Italy and the UK contributed 5 and 1, respectively, although the difference was <0.5 at 9 to 13+6 weeks’ gestation (Fig 3). We investigated the effect of removing these potential outlying sites from the dataset used to construct the centiles: The effect was minimal, so all were included (Fig A and Table B in S3 Text).

Fig 2

SSD for systolic blood pressure in the FGLS of the INTERGROWTH-21st Project.

FGLS, Fetal Growth Longitudinal Study; SBP, systolic blood pressure; SD, standard deviation; SSD, standardised site difference.

Fig 3

SSD for diastolic blood pressure in the FGLS of the INTERGROWTH-21st Project.

DBP, diastolic blood pressure; FGLS, Fetal Growth Longitudinal Study; SD, standard deviation; SSD, standardised site difference.

For all women, the median systolic blood pressure was lowest at 12 weeks’ gestation: 111.5 (95% CI 111.3 to 111.8) mmHg rising to a maximum of 119.6 (95% CI 118.9 to 120.3) mmHg at 40 weeks’ gestation, a difference of 8.1 (95% CI 7.4 to 8.8) mmHg. Diastolic blood pressure decreased from 12 weeks’ gestation: median 69.1 (95% CI 68.9 to 69.3) mmHg to 68.5 (95% CI 68.3 to 68.7) mmHg at 19+5 weeks’ gestation, a change of −0.6 (95% CI −0.8 to −0.4) mmHg. Diastolic blood pressure then increased to a maximum of median 76.3 (95% CI 75.9 to 76.8) mmHg at 40 weeks’ gestation, a minimum (at 19+5 weeks) to maximum difference of 7.8 (95% CI 7.3 to 8.2) mmHg.

Fig 4 represents the smoothed, pregnancy-specific, third, 10th, 50th, 90th, and 97th centiles for systolic and diastolic blood pressure. Gestational age-specific values for the smoothed centiles and a plot of the smoothed centiles with associated 95% CI can be found in Table C and Fig B in S3 Text.

Fig 4

Smoothed centiles for systolic and diastolic blood pressure in mmHg; third, 10th, 50th, 90th, and 97th centiles.

Other analyses

A sensitivity analysis of normotensive pregnancies (excluding women who developed hypertension, defined as systolic ≥140 mmHg or diastolic ≥90 mmHg, at any follow-up visit) showed similar blood pressure patterns (Fig C in S3 Text).

Fig 5 shows the absolute change from baseline blood pressure for all women. Systolic blood pressure fell by >14 mmHg or diastolic blood pressure by >11 mmHg from baseline in fewer than 10% of women at any gestational age. Systolic blood pressure fell by >16 mmHg or diastolic blood pressure by >11 mmHg in only 3% of women at 40 weeks’ gestation. Under 10% of women increased their systolic blood pressure by >24 mmHg or diastolic blood pressure by >18 mmHg at any gestational age. Less than 3% of women increased their systolic blood pressure by >34 mmHg or diastolic blood pressure by >26 mmHg.

Fig 5

Changes from baseline for both systolic and diastolic blood pressure from 16 weeks’ gestation for third, 10th, 50th, 90th, and 97th centiles.

Smoothed centiles for blood pressure by gestational age, and change from baseline blood pressure, depending on quartile of baseline blood pressure at study enrolment are presented (Figs D and E in S3 Text). The figures demonstrate a strong regression to the mean effect.

Discussion

Our population-based study includes over 4,000 healthy women from 8 diverse countries, which allowed construction of international, evidence-based, gestational age-specific centiles for blood pressure throughout pregnancy. Systolic blood pressure rose through pregnancy, with no mid-second trimester drop. The diastolic blood pressure nadir at 19+5 weeks’ gestation was only 0.6 mmHg lower than measures taken at study entry <14 weeks’ gestation. A decrease of >14 mmHg from the baseline systolic or diastolic blood pressure was unusual (<10% of all women), particularly in the latter stages of pregnancy. The average increase in term blood pressure from baseline was <10 mmHg for both systolic and diastolic measures. Systolic blood pressure fell by >14 mmHg or diastolic blood pressure by >11 mmHg from baseline in fewer than 10% of women at any gestational age. Fewer than 10% of women increased their systolic blood pressure by >24 mmHg or diastolic blood pressure by >18 mmHg at any gestational age.

Interpretation

Our study allows clinicians to interpret blood pressure in pregnancy in the light of international gestational age-specific centiles. It shows that the initial blood pressure in pregnancy can be used to facilitate interpretation of subsequent measures. These findings should aid clinicians in recognising when a pregnant woman is deviating from “normal” values. The proportion of total variance attributed to population differences between sites was <7%, and removing potentially outlying sites did not alter our findings, supporting the position that population-specific ranges for blood pressure in pregnancy are not required.

Comparison with other studies

Blood pressure

Our findings are contrary to much published literature upholding a clinically significant mid-second trimester drop. Data underlying this view are often dated [9,10], routinely collected [21,22], single centre [9,10], and based on non-standardised measurement of blood pressure [9,10] or devices not ratified for use in pregnancy [10,21-23]. Larger, routinely acquired birth cohorts from single geographical regions show smaller drops [12,24]. More recent, prospective, standardised studies refute this dogma [25,26]. Our systematic review, including over 36,000 women, found an almost identical progressive rise in systolic blood pressure and approximately 1 mmHg mid-second trimester drop in diastolic blood pressure [27]. Taken together, clinically significant drops in population blood pressure from booking to delivery clearly do not occur in modern practice.

Confusion may have arisen because studies use different definitions of baseline blood pressure. Where prepregnancy blood pressure (rather than the first blood pressure taken in pregnancy) is used as the baseline, a small drop is generally seen mid-second trimester [11,23]. Although physiologically interesting, recent prepregnancy blood pressures are not usually available. Blood pressure patterns during pregnancy, as revealed in our study, are probably more important clinically.

Women in the lowest quartile of booking blood pressure demonstrated the largest rise in blood pressure, while the highest quartile had the greatest range of likely decreases, showing regression to the mean. These prospective findings add to previous work from routinely acquired data [12].

Strengths and limitations of study

To our knowledge, this is the first study to collect blood pressure data from across the world using the prescriptive approach recommended by WHO for construction of international standards. This is also the largest prospective study using an automated method of blood pressure measurement with a machine validated in pregnancy.

By adopting these approaches to collect data prospectively from healthy women in a population-based study involving 8 geographically diverse sites, we are confident that the international centiles are both robust and representative of women of optimal health, nutrition, education, and socioeconomic status.

Limitations

The study has limitations. The lack of prepregnancy blood pressure data may disguise a relative drop in blood pressure in early pregnancy. However, as a prepregnancy measure is rarely available in routine clinical practice, comparison with blood pressure in early pregnancy contributes to clinical applicability.

We did not exclude the few women who developed gestational hypertension (3%) or preeclampsia (<1%), rather, we chose to demonstrate that excluding these women did not affect our findings (Fig C in S3 Text). The large size of the study made it impractical to define the time of day at which blood pressure was measured to allow exploration of circadian effects. In our study, blood pressure was not measured in duplicate; however, this mirrors clinical practice. The INTERGROWTH-21st Project recruited women with a BMI <30 kg/m2; therefore, the applicability of the findings to women with a BMI 330 kg/m2 is uncertain. Further work is needed to determine how knowledge of these centiles affects the detection of deteriorating health in pregnant women.

Policy implications

There is an indisputable need for pregnancy-specific early warning scores that incorporate blood pressure changes [5]. Current national definitions of severe maternal sepsis either do not include hypotension as a contributory factor (UK Obstetric Surveillance System [2]) or stipulate a physiologically extreme drop in systolic blood pressure >40 mmHg (UK Sepsis Trust [28]). We show that it is highly abnormal for a healthy woman to demonstrate a systolic or diastolic blood pressure drop of half this magnitude, making a strong case for utilising less severe thresholds for systolic hypotension in maternal sepsis definitions. Current MOEWS systems are derived from expert opinion [29], but could be better evidenced using blood pressure centile thresholds, an approach shown to be effective in nonpregnant adults [30].

Conclusions

We present international, gestational age-specific centiles for blood pressure based on a healthy population of low-risk women with good pregnancy outcomes. We show clear limits for acceptable change in blood pressure during pregnancy, which should help clinicians determine patients with abnormal blood pressure rises and falls. Our findings challenge the frequently quoted mid-second trimester drop in blood pressure, advocating for a higher index of clinical suspicion when a woman presents with a “lower than booking” blood pressure, especially in late pregnancy. These gestational age-specific centiles should help build an adaptive, intelligent, evidence-based MOEWS to allow earlier recognition of the unwell pregnant woman.

Transparency declaration

PW guarantees that the manuscript is an honest, accurate, and transparent account of the study being reported and that no aspects have been omitted.

STROBE, Strengthening the Reporting of Observational Studies in Epidemiology.

(DOC)

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Sample size calculation.

(DOCX)

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Statistical analysis plan.

(XLSX)

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Supporting information.

Table A in S3 Text: Baseline characteristics for women enrolled in the FGLS. Table B in S3 Text: All sites and individual site means (SD) for DBP and SBP of all women. Fig A in S3 Text: Plot to illustrate sensitivity analysis for excluding potential site outliers; SBP and DBP according to gestational age for third, 50th, and 97th centiles. Table C in S3 Text: Smoothed centiles for SBP and DBP according to gestational age for third, 10th, 50th, 90th, and 97th centiles (95% CI). Fig B in S3 Text: Smoothed centiles for SBP and DBP in mmHg; third, 10th, 50th, 90th, and 97th centiles with corresponding 95% confidence intervals. Fig C in S3 Text: Smoothed centiles for SBP and DBP in mmHg excluding women (n = 132) who developed hypertension (systolic BP ≥140 or diastolic BP ≥90); third, 10th, 50th, 90th, and 97th centiles. Fig D in S3 Text: SBP and DBP from 16 weeks’ gestation onwards for quartiles according to baseline blood pressure (third, 10th, 50th, 90th, and 97th centiles). First quartile 76–105/40–64 mmHg; second quartile 106–111/65–70 mmHg; third quartile 112–119/71–75 mmHg; fourth quartile ≥120/76 mmHg). Fig E in S3 Text: Change in systolic and DBP during pregnancy by quartiles of baseline blood pressure at study entry at 9–13+6 weeks’ gestation. DBP, diastolic blood pressure; FGLS, Fetal Growth Longitudinal Study; SBP, systolic blood pressure; SD, standard deviation; SSD, standardised site difference.

(DOCX)

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Contributions to membership of the INTERGROWTH-21st and its Committees.

INTERGROWTH-21st, International Fetal and Newborn Growth Consortium for the 21st Century.

(DOCX)

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21 Dec 2020

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Please restructure the start of the Discussion section so that the first paragraph provides a summary of the study's main findings.

Throughout the text, please adapt reference call-outs as follows: "... mid-trimester [11,23].".

Please remove information on funding and competing interests from the title page and from the end of the main text. In the event of publication, this information will appear in the article metadata, via entries in the submission form.

Please ensure that all references contain full access information, e.g., reference 3.

Please supply a completed STROBE checklist with your revision as a supplementary file, labelled "S1_STROBE_Checklist" or similar and referred to as such in your methods section. In the checklist, please refer to individual items by section (e.g., "Methods") and paragraph number rather than by line or page numbers, as the latter generally change in the event of publication.

Comments from the reviewers:

*** Reviewer #1:

This report presents the secondary analysis of a prospective, longitudinal, observational cohort study (2009-16) across eight diverse urban areas in Brazil, China, India, Italy, Kenya, Oman, United Kingdom, and United States.

The stated primary aim of the analysis was to describe systolic and diastolic cohort blood pressure patterns in healthy pregnancy. The authors have conducted sensitivity analyses to assess the effect of excluding women who developed hypertension (defined as systolic ≥140 mmHg or diastolic ≥90 mmHg at any follow-up visit), and constructed international gestational age-specific centiles for blood pressure in women who remained normotensive (blood pressure <140/90 mmHg).

Comments:

This study is reported to follow STROBE guidelines. Can the authors please supply a copy of their STROBE checklist in the supplementary material?

Given the extent of the relevant supporting documentation, in terms of protocols, data collection forms, and electronic transfer strategies, it is perhaps appropriate that the authors site where readers can access these (www.intergrowth21.org), rather than include copies within the supplementary material.

"Statistical considerations focused on the precision and accuracy of a single centile and regression based reference limits. FGLS established an average sample of 500 pregnant women per study site, after exclusion of complicated pregnancies (approximately 3%) and those lost to follow-up (estimated to be 3%). This sample size was adequate to explore site-specific differences (18). "

Can more detail on these sample size calculations please be provided by the authors in brief within the supplementary material?

"We constructed International, gestational age-specific, smoothed centiles for blood pressure, i.e. 3rd, 10th, 50th, 90th and 97th centiles with corresponding 95% confidence intervals, following WHO recommendations (19). "

The analytical approach applied is robust and rigorous, with a summary of techniques provided in the Methods section.

The statistical methodology is technically appropriate and recommended practice for the data type, research question and study context in hand, including that applied for the subgroup and post hoc analyses.

*** Reviewer #2:

I appreciated reviewing this manuscript, which represents an important topic of interest in prenatal/antenatal care. The INTERGROWTH-21st Study has brought very critical evidence to obstetrics, and this manuscript promises to continue this trend. However, I have some concerns about it in its current form.

1. Throughout the paper, you've used the term "mid-trimester". It may be a case of minor linguistic differences, but to me this term means "in the middle of any trimester" and not in the middle of a specific trimester. At one point you do use "mid-second trimester" and it would be clearer to an international audience to use this phrasing each time.

2. The Research in Context section is meant for general audiences, but is currently very jargony. I think that the Introduction and Discussion of the paper use more accessible language that could be paraphrased here.

3. In the Introduction, the MOEWS needs to be briefly described where it is introduced.

4. The Methods section is in need of reorganization. All of the subsections that are about the participants (Participants, Bias, Study size) should be together, and all of the sections that are about the analyses (Variables, Quantitative variables, [neither of which, I would argue, describe variables], Other analyses, and Statistical methods) should be together. After rearranging, the grouped subsections will need to be edited to remove redundancy and to more clearly describe the flow of your analysis plan as it is presented in the Results and Supplements.

5. The figure designs need improvement. The symbols representing the Standardized Site Differences in Figure 2 are difficult to discern and need to be enlarged. Also in Figure 2, the SBP plot should go before the DBP plot to be consistent with the title and the presentation of the findings. In many of the remaining figures, SBP and DBP are not clearly distinguished from each other. The color scheme for most of the figures (3, 4, S3-5.2) is not particularly aesthetic, and it is not clear to me why color blocks were used instead of lines.

*** Reviewer #3:

Reviewer comments:

Abstract:

The authors have performed a unique analysis generating gestational age-specific centiles using blood pressure data from a population-based study including women from across the world. Their results are important as they provide information on international standards. Moreover, these results provide insight into physiological blood pressure changes in pregnancy. Overall, this is a clearly designed and very well-written study and the fact that it is prospective adds value to the data. The study uses strong statistical methods and analyses.

I only do have some minor comments:

Minor:

- Abstract:

Results section: Systolic blood pressure: …. , difference (95% CI) 8.1 (7.4 to 8.8) mmHg. This sentence is unclear. At least add the word "a" as is written in the results section. However, the authors preferably state more clearly only a difference in systolic blood pressure of 8.1 mmHg (95% CI: 7.4-8.8) between 12 weeks' gestation and 40 weeks' gestation is found.

- Description results:

I suggest to adapt the description of the results to: Median (then value) and subsequent (95% CI: values) which is easier to read and then understand the results.

- Conclusions:

The conclusion that these data provide a strong basis for constructing… (line) is not supported by these data. Hence, in the abstract the authors should use describe it as accordingly in the main paper-discussion: (Line 480-482): These gestational age-specific centiles should help build an….

-

Results:

Line 355: minimum to maximum difference. The authors should also refer to and add the gestational age then: is it second to third trimester?

Discussion:

Interpretation:

Line 408-409: These findings should aid clinicians in recognizing when a pregnant woman is becoming unwell.

I disagree with this sentence as these findings as for now only help to recognize deviations from normal values.

The authors should change this interpretation of their data as they have not investigated that their values aid in recognizing when a pregnant woman is becoming unwell.

Furthermore, the phrase becoming unwell is too vague. They should state more specifically what they mean by this word.

Additionally, they should state more clearly that it still needs to be thoroughly investigated these values are of additional value for the detection of clinically ill women. Then only, subsequently, as they mention in their conclusion the results will help build an MOEWS to allow earlier recognition.

Limitations:

With the aim of this study to describe blood pressure patterns in a healthy pregnancy women (with an increased risk of ) developing complications are excluded. The authors succeeded as for example a low incidence of gestational hypertension and preeclampsia is reported. They furthermore demonstrated in a sensitivity analysis that exclusion of these women did not affect their results.

However, they should mention in their limitations that the strict inclusion criteria (e.g age 18-35 years, BMI < 30) as described in their methods may contribute to less generalizability of their gestational age-specific centiles for blood pressure. Specifically, taking their future conclusion into account as their results should help clinicians determine patients with abnormal blood pressure rise and falls.

Limitations:

The authors indeed mention that lack of pre-pregnany data may disguise first-trimester changes. They however then jump to the following conclusion (line 453-454): comparison with blood pressure in early pregnancy has greater clinical applicability.

I think this statement is overrated and this conclusion cannot be drawn as there was no comparison with pre-pregnancy data as these are lacking.

Hence, suggest to change this sentence to: in routine clinical practice, blood pressure in early pregnancy contributes to clinical applicability.

***

Any attachments provided with reviews can be seen via the following link:

[LINK]

Submitted filename: PLOS_Medicine_comments_210215.docx

Click here for additional data file.

22 Mar 2021

Submitted filename: Response to Editors Letter.docx

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24 Mar 2021

Dear Dr. Green,

Thank you very much for re-submitting your manuscript "International gestational age-specific centiles for blood pressure in pregnancy from the INTERGROWTH-21st Project: a longitudinal cohort study in eight countries" (PMEDICINE-D-20-06147R2) for consideration at PLOS Medicine.

I have discussed the paper with editorial colleagues and our academic editor and I am pleased to tell you that, provided the remaining editorial and production issues are dealt with, we expect to be able to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

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Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org

------------------------------------------------------------

Requests from Editors:

The current version of the paper has a notable level of text matching with a published paper (Ohuma et al) on the INTERGROWTH project, mainly in the Methods section. We ask you to reword the relevant sections of the text to reduce this.

Please make arrangements for data deposition in a suitable publicly-accessible repository, and update the data statement in your paper.

In the title, please move "in 8 countries" before the colon.

Please remove "only" at line 66.

At line 68 and any other instances, we suggest rephrasing "... dropped their blood pressure" (to, e.g., "Systolic blood pressure fell in fewer ...").

Please bullet the points in the Author summary, aiming for 3 subsections of 3 points each, comprising 1-2 short sentences.

If participants' provision of informed consent is not mentioned in the Methods section, please add this.

Please adapt the label for the STROBE checklist to "S1_STROBE_Checklist" or similar and refer to it by this label in the text.

Throughout the text, please use the style "8 diverse countries", except at the start of sentences (e.g., "Eight diverse countries ...").

Please remove the information on copyright from the end of the main text (the paper will be published under a CC-BY licence).

Please remove the information on the INTERGROWTH groups from the end of the main text (this can be transferred to a Supplementary file, if you wish).

***

26 Mar 2021

Submitted filename: Response to Editors Letter Resubmission 26.3.21.docx

Click here for additional data file.

3 Apr 2021

Dear Dr Green,

On behalf of my colleagues and the Academic Editor, Prof Persson, I am pleased to inform you that we have agreed to publish your manuscript "International gestational age-specific centiles for blood pressure in pregnancy from the INTERGROWTH-21st Project in 8 countries: a longitudinal cohort study" (PMEDICINE-D-20-06147R3) in PLOS Medicine.

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Sincerely,

Richard Turner, PhD

Senior Editor, PLOS Medicine

rturner@plos.org